NMR spectroscopy has been used to concurrently measure very low density lipoprotein (VLDL), low density lipoproteins (LDL) and high density lipoproteins (HDL) as VLDL, LDL and HDL particle subclasses from in vitro blood plasma or serum samples. See, FIG. 1 and U.S. Pat. Nos. 4,933,844 and 6,617,167, the contents of which are hereby incorporated by reference as if recited in full herein. Generally stated, to evaluate the lipoproteins in a blood plasma and/or serum sample, the amplitudes of a plurality of NMR spectroscopy derived signals within a chemical shift region of the NMR spectrum are derived by deconvolution of the composite methyl signal envelope or spectrum to yield subclass concentrations.
The subclasses are represented by many (typically over 60) discrete contributing subclass signals associated with NMR frequency and lipoprotein diameter as shown in FIG. 2. As shown in FIG. 3, the NMR evaluations can interrogate the NMR signals to produce concentrations of different subpopulations shown as seventy-three (73) discrete subpopulations, 27 for VLDL, 20 for LDL and 26 for HDL. These sub-populations can be further characterized as associated with a particular size range within the VLDL, LDL or HDL subclasses.
Conventionally, a patient's overall risk of coronary heart disease (CHD) and/or coronary artery disease (CAD) has been assessed based on measurements of cholesterol content of a patient's LDL and HDL particles (LDL-C, HDL-C) rather than the numbers of these particles. These two risk factors are used to assess a patient's risk, and treatment decisions may be made to reduce the “bad” cholesterol (LDL-C) or increase the “good” cholesterol (HDL-C).
In the past, the LipoProfile® “advanced” lipoprotein test panels from LipoScience, Inc. have typically included a total high density lipoprotein particle (HDL-P) measurement (e.g., HDL-P number) and a total low density lipoprotein particle (LDL-P) measurement (e.g., LDL-P number). The particle numbers represent the concentration in units such as nmol/L (for LDL-P) or μmol/L (for HDL-P). A total HDL-P number, the sum of the concentration values of each of the HDL-P subclasses, can provide CHD risk assessment information that may be more accurate than or complement HDL-C.
It is believed that LDL-P is a better indicator of risk of CHD relative to LDL-C as well as for therapy decisions. However, there are still open questions about the different functions of HDL and how to best evaluate CHD risk associated with a patient's HDL. See, e.g., Kher at el., Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Athersclerosis, N Engl. J. Med. 364: 127-135 (Jan. 13, 2011); Navab et al., HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms, Nat. Rev. Cardiol., 8, 222-232 (2011); and Alan Fogelman, When good cholesterol goes bad, Nat. Med., Vol. 10, No. 9, pp. 902-903 (September 2004), the contents of which are hereby incorporated by reference as if recited in full herein. The mechanisms by which HDL can be protective or non-protective as associated with a person's risk of developing atherosclerosis or heart disease are complex and multifactorial. See, Farmer et al., Evolving Concepts of the Role of High-Density Lipoprotein in Protection from Athersclerosis, Curr Atheroscler Rep (2011) 13:107-114, the contents of which are hereby incorporated by reference as if recited in full herein.
Van der Steeg et al. have carried out studies showing that higher HDL-C levels when observed with a preponderance of large HDL particles are not inversely related to the risk of CAD. Indeed, higher HDL-C proved to be a major cardiac event risk factor when adjusted for age, gender, smoking, apoA-1 and apoB. Van der Steeg et. al. concludes that when apoA-1 and apoB are kept constant, HDL-C and HDL particle size may confer risk at very high values. See, Van der Steeg et. al., High-Density Lipoprotein Cholesterol, High Density Lipoprotein Particle Size, and Apolipoprotein A-1: Significance for Cardiovascular Risk, JACC, Vol. 51, No. 6, 2008 (634-642), the contents of which are hereby incorporated by reference as if recited in full herein.
There remains an unmet clinical need for tests that can identify those individuals that have high levels of HDL, e.g., large HDL-P and that may be at increased risk of a cardiac event.